Impaired insulin secretion in a mouse model of ataxia telangiectasia

• Published in: American journal of physiology: endocrinology and metabolism 2007-07, Vol.293 (1), p.E70-E74
• Main Authors: Miles, Philip D, Treuner, Kai, Latronica, Marc, Olefsky, Jerrold M, Barlow, Carrolee
• Format: Article
• Language: English
• Subjects: Aging - metabolism; Animals; Ataxia Telangiectasia - complications; Ataxia Telangiectasia - metabolism; Ataxia Telangiectasia - pathology; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - genetics; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - genetics; Disease Models, Animal; DNA damage; DNA-Binding Proteins - genetics; Female; Genes; Glucose; Glucose Intolerance - genetics; Insulin - metabolism; Insulin Resistance - genetics; Insulin Secretion; Male; Mice; Mice, Knockout; Mutation; Neurological disorders; Protein-Serine-Threonine Kinases - genetics; Rodents; Tumor Suppressor Proteins - genetics
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00259.2006

1 Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla; and 2 Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California Submitted 29 May 2006 ; accepted in final form 14 December 2006 Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the A-T mutated (ATM) gene. The gene encodes a serine/threonine kinase with important roles in the cellular response to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although these functions might explain the cancer predisposition of A-T patients, the molecular mechanisms leading to glucose intolerance and diabetes mellitus (DM) are unknown. We have investigated the pathogenesis of DM in a mouse model of A-T. Here we show that young Atm -deficient mice show normal fasting glucose levels and normal insulin sensitivity. However, oral glucose tolerance testing revealed delayed insulin secretion and resulting transient hyperglycemia. Aged Atm –/– mice show a pronounced increase in blood glucose levels and a decrease in insulin and C-peptide levels. Our findings support a role for ATM in metabolic function and point toward impaired insulin secretion as the primary cause of DM in A-T. Atm –/– mice; diabetes mellitus Address for reprint requests and other correspondence: C. Barlow, BrainCells, Inc., 10835 Road to the Cure, Ste. 150, San Diego, CA 92121 (e-mail: cbarlow{at}braincellsinc.com )